tbuckley/cabot-search huggingface dataset:
Abstract 2666: Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin or paclitaxel for treatment of cervical cancer
Authors: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg Palmer, Angeles A. Secord
Journal: Cancer Research (2023)

Abstract Introduction: Cervical cancer is a serious health problem despite the fact it is highly preventable. Early-stage cervical cancer treatment often involves surgery; however advanced, recurrent, or metastatic cases require systemic therapy. Chemotherapy, mainly cisplatin, is the most commonly used systemic therapy for this cancer type. Combination regimens may be needed in the recurrent or metastatic settings, with first-line treatments including cisplatin with paclitaxel. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Concomitant treatment with TTFields and cisplatin or paclitaxel has shown benefit in other tumor types. In the current in vitro study, we tested the effectiveness of TTFields for the treatment of cervical cancer, and the possible benefit of applying TTFields together with first-line treatments for cervical cancer. Methods: Human cervical cancer cell lines - squamous cell carcinoma Ca Ski and SiHa cells, and adenocarcinoma HeLa cells - were treated with TTFields (72 h, 1 V/cm RMS) at frequencies of 100 to 400 kHz, and tested for cell count. For examining the efficacy of TTFields concomitant with cisplatin or paclitaxel, various doses of the drugs were applied together with TTFields (200 kHz), followed by measurements of cell count, colony formation, and apoptosis. Overall effect was defined as the product of percent reductions in cell count and colony formation. Results: TTFields treatment reduced cell count in all tested cervical cancer cell lines. 200 kHz were found to be effective and were used throughout the experiments. Dose response effects were seen with cisplatin or paclitaxel, and were augmented when TTFields were co-applied to the cells. Conclusions: These preclinical data suggest that TTFields may be an effective treatment against cervical cancer, and that applying them concomitantly with first-line treatment for this malignancy may provide enhanced effectiveness. Citation Format: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg Palmer, Angeles A. Secord. Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin or paclitaxel for treatment of cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2666.
Abstract 3795: Deciphering the <i>in vivo</i> roles of a novel long non-coding RNA in chronic lymphocytic leukemia and Richter syndrome
Authors: Swati Mohapatra, Erik Knutsen, Mihai Iurascu Gagea, Linda Fabris, George Adrian Calin
Journal: Cancer Research (2023)

Abstract The ultraconserved regions (UCRs) are the genomic segments manifesting perfect conservation between the orthologous genomes of humans, rats, and mice that get transcribed into mono-exonic long non-coding RNAs (lncRNAs) known as transcribed ultraconserved regions (T-UCRs). Increasing evidence demonstrates the importance of T-UCRs in human cancers, however, their involvement in the pathogenesis of Chronic Lymphocytic Leukemia (CLL) is poorly understood. Our lab has recently identified a lncRNA transcribed from a UCR and named it TRUC-16 (Translational Regulatory UltraConserved gene affecting p16), which is overexpressed in CLL and correlates with treatment-free survival. We have developed a transgenic C57BL6 mouse model to overexpress TRUC-16 in B cells. We monitored the number and development of B cell subsets over time in peripheral blood and lymphoid organs (lymph nodes, spleen, and bone marrow), and performed immunophenotyping to assess clonality and proportion of the cells considered to be the origin for CLL (i.e. B1 cells and IgM memory B cells that are CD5+). We followed mice survival (n=10 for each gender) and performed necropsy with histopathologic and immunophenotypic analysis. If blood sampling suggests developing a CLL-like state, we will monitor for evolution to Richter Syndrome by flow cytometry analysis and biochemistry markers. We have validated the TRUC-16 overexpression specific to the B-cell compartment in the mice cohorts and have observed lymphoma in several organs. Interestingly, TRUC-16 overexpressing mice showed significantly higher splenic weights compared to controls. The mice were found to develop adulthood lymphoma that we are now analyzing molecularly and phenotypically. We are planning to further characterize the subtype of lymphoma by utilizing specific diagnostic markers through immunohistochemistry and flow cytometry. This is the first-ever transgenic mice modeling overexpression of UCR in the context of cancer. Validation of the functional correlation between the TRUC-16 phenotype and CLL patients’ clinical data will provide a valuable resource to pursue a multitude of preclinical studies to find targets that might help better understand the disease pathophysiology. Citation Format: Swati Mohapatra, Erik Knutsen, Mihai Iurascu Gagea, Linda Fabris, George Adrian Calin. Deciphering the in vivo roles of a novel long non-coding RNA in chronic lymphocytic leukemia and Richter syndrome. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3795.
Abstract 5957: Chemotherapy-induced extracellular matrix remodeling in HGSOC
Authors: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill
Journal: Cancer Research (2023)

Abstract In this study we explored the effects of chemotherapy on the extracellular matrix of high-grade serous ovarian cancer metastasis (HGSOC) at structural-textural protein level and transcriptionally, in order to identify the microenvironmental features that accompany a successful response. We studied two murine orthotopic, transplantable syngeneic models of HGSOC, one that displays excellent response to carboplatin/paclitaxel (60577) and one that is resistant to treatment (HGS2)1. Using immunohistochemistry, we stained omental tumors from both models for the ECM components fibronectin (FN1), collagen 1A1 (COL1A1) and versican (VCAN), also using Masson’s Trichrome to stain for collagen. We analyzed their abundance, textural features (Haralick features) and structure with the image analysis softwares, QuPath and TWOMBLI respectively. A compilation of 44 ECM metrics, which we named the “structure index”, correlated with response to chemotherapy, as measured by reduction in omental tumor weight. In parallel, we performed RNAseq on the omental tumors, identifying clusters of genes that change over time with chemotherapy treatment of the responsive model 60577, while the chemoresistant model HGS2 displayed limited alteration of gene expression. We integrated RNAseq and ECM structure and texture data, and showed the structure index was correlated with 144 core matrisome genes. To identify potential therapeutic targets, we then focused our study on genes that remained highly expressed in resistant tumors post chemotherapy, but were originally low or decreased with treatment in the sensitive tumors. Members of the LOX and P4HA family were found amongst these genes. We confirmed by immunohistochemical analysis that expression of LOX, LOXL2, P4HA1 and P4HA2 was downregulated by chemotherapy in the 60577 chemo-sensitive tumors while their levels remained relatively unaffected in the resistant HGS2 tumors. This study refines our understanding of the mechanisms of microenvironmental chemoresistance in HGSOC, highlighting putative therapeutic targets to increase the efficacy of platinum-based chemotherapy in ovarian cancer. 1 Maniati, E. et al. Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment. Cell Rep 30, 525-540.e527, doi:10.1016/j.celrep.2019.12.034 (2020). Citation Format: Panoraia Kotantaki, Florian Laforêts, Eleni Maniati, Chiara Berlato, Anna Malliouri, Michael John Devlin, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Frances R. Balkwill. Chemotherapy-induced extracellular matrix remodeling in HGSOC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5957.
Abstract 3192: Antitumor activity of ex vivo expanded tumor antigen priming cytotoxic T cells against malignant melanoma
Authors: Jonggwon Choi
Journal: Cancer Research (2023)

Abstract Background: Dendritic cells have a unique ability to pick up antigen from tissues and migrate to the lymph nodes where they can cross-present cell-associated antigens with CD8+ T cells by MHC class I. Cytotoxic T lymphocytes remove malignant cells through recognition by T cell receptors of specific antigenic peptides that appear on the surface of cancer cells by the major histocompatibility complex class I/beta-2-microglobulin complex. In this study, we show that naive CD8+ T cells against the melan A antigens cells primed by DCs loaded with melan A antigens are able to kill malignant melanoma cell line (SK-MEL-28). Methods: Peripheral blood mononuclear cells and Co-culture dendritic cells-T cells were seeded and MART-1 (100 ng/ml) reacted for 20 hours. ELISPOT ASSAY analyzes the degree of secretion of IFN-γ induced by Melan-A/MART-1 peptide stimulation in DC-T (1st week). In addition, the subtype analysis of T cells through FACS and the cytotoxicity activity of T cells was measured by tumor cell impedance with AXION. Results: In ELISPOT ASSAY, it was observed that the number of positive spots increased significantly over time compared to 1st week. In FACS result analysis, CD4+ and CD8+ T cells increased, CD4+ T cell was observed as a dominant T cell subtype. As a result of cell impedance assay using Axion, it was observed that the number of tumor cells (SK-MEL-28) decreased according to the CTL:T ratio. In particular, cytotoxicity was observed immediately after co-culture and gradually showed cytotoxicity up to 72 hours. Conclusion: Our study demonstrates that DCs loaded with killed allogeneic melanoma cells can cross-prime cytotoxic T cell which is specific for melan A antigen. In the future, additional T-cell studies targeting neoantigen and clinical studies applied to solid cancer patients will be conducted. Keywords: Dendritic cell, CD4+/CD8+ T cell, Melan A antigen, Malignant melanoma Citation Format: Jonggwon Choi. Antitumor activity of ex vivo expanded tumor antigen priming cytotoxic T cells against malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3192.
Abstract 1620: Identification of a molecular degrader targeting the AR-V7 splice variant
Authors: Yuan Liu, Bo Lin, Mads B. Larsen, Irene Alfaras, Jason R. Kennerdell, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen
Journal: Cancer Research (2023)

Abstract Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bound to AR-V7. One such molecule, CL-AR-100, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. This compound did not affect the expression of other structurally related ligand-activated nuclear receptors. In prostate cancer cell lines expressing AR-FL, CL-AR-100 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, CL-AR-200 inhibited the growth of 22RV1 cells (IC50=0.3uM), a cell line that predominantly expresses AR-V7. In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth. These results thereby identify a small molecule molecular degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer. Citation Format: Yuan Liu, Bo Lin, Mads B. Larsen, Irene Alfaras, Jason R. Kennerdell, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a molecular degrader targeting the AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1620.
Abstract 175: Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma
Authors: Daryl J. Phuong, Amanda P. Armstrong, Andrea Flesken-Nikitin, Alexander Y. Nikitin, John C. Schimenti
Journal: Cancer Research (2023)

Abstract High grade serous carcinoma (HGSC) is the most common and deadly form of ovarian cancer. Although HGSC can arise from cells in the ovarian surface epithelium (OSE) or fallopian (oviductal) tubal epithelium (TE), the cell state and genetic alterations for HGSC initiation and progression remains unclear. Previous studies with cell type-specific mouse knockouts found inconsistencies in tumorigenesis and chemoresistance. These data can be explained if specific gene signatures in specific cell types have varied tumorigenic potential and chemoresistance. To determine specific gene combinations necessary for OSE and TE malignant transformation, we designed a CRISPR knock out (KO) mini-library against commonly mutated genes of HGSC. Our previous results revealed efficient gene combinations for ex vivo OSE transformation events and a preference for OSE stem cell transformation. To build on our previous studies, we extended our screening methods into TE cells. Our studies utilize an organoid approach to identify the most cancer-prone cell populations. They also test if cell differentiation state determines a specific set of genetic alterations necessary for HGSC initiation. Our screening platform has the potential to determine whether specific genetic alterations in specific cell types are required for malignant transformation. Additionally, our results may improve on previous models of HGSC initiation and progression. Citation Format: Daryl J. Phuong, Amanda P. Armstrong, Andrea Flesken-Nikitin, Alexander Y. Nikitin, John C. Schimenti. Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 175.
Abstract 2563: Identifying BCLAF1 as a downstream effector of p85β in ovarian cancer
Authors: Panpan Wang, Ling Rao, Victor CY Mak, Lydia WT Cheung
Journal: Cancer Research (2023)

Abstract The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is dysregulated in a broad spectrum of human cancers. Genomic alterations of the pathway members can cause cell transformation and tumorigenesis. The class IA PI3K is a dimeric enzyme composed of a catalytic subunit and a regulatory subunit to initiate AKT activation, with the two major regulatory subunits being p85α and p85β. Apart from sharing a canonical function in binding to and stabilizing p110α, we and the others have demonstrated that p85α and p85β carry distinct activities. We have recently reported an oncogenic role of p85β in ovarian cancer cells. In this study, we analyzed multiple omics data to further explore the oncogenic mechanism of p85β. BCL2 Associated Transcription Factor 1 (BCLAF1) was identified as a downstream effector of p85β. We found that the protein level of BCLAF1 was consistently decreased upon PIK3R2 silencing in ovarian cancer cell lines, and that the decrease could be reversed after PIK3R2 overexpression. Importantly, knockdown of BCLAF1 reduced the oncogenicity of p85β, whereas BCLAF1 overexpression promoted cell viability, cell invasion and migration. Accompanied with the increase in total protein level was enhanced phosphorylation of multiple serine residues of BCLAF1. Functional analysis of the serine residues by expressing the phosphorylation-defective mutants suggested that Ser161, Ser512 and Ser531 are critical for BCLAF1 oncogenic functions in ovarian cancer. Together, the findings reveal a new downstream effector by which p85β exerts its oncogenic effects in ovarian cancer. Citation Format: Panpan Wang, Ling Rao, Victor CY Mak, Lydia WT Cheung. Identifying BCLAF1 as a downstream effector of p85β in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2563.
Abstract 6129: The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice
Authors: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini
Journal: Cancer Research (2023)

Abstract In cancer cells, the proapoptotic proteins caspase-9 and PP2A interaction prevents them to play their role in apoptosis. PEP-010, a drug candidate developed by PEP-Therapy, a French Biotech company, is a proapoptotic peptide targeting and disrupting this interaction leading to restoration of the apoptotic cascade. PEP-010 is an innovative bifunctional peptide. It penetrates into cells thanks to its cell penetrating part and specifically disrupts the caspase-9/PP2A interaction thanks to its interfering part. PEP-010 is currently in Phase I a/b multicenter clinical trial for the treatment of advanced solid tumors.To the aim of screening different potential therapeutic targets, to investigate the molecular mechanism-of-action of PEP-010 and to identify potential pharmacodynamic biomarkers, we have tested PEP-010 efficacy on several cell models of different tumor origins. By the Annexin V/Propidium Iodide staining and flow cytometry analysis, we found that PEP-010 induces apoptosis in most of the tested models. One possible mechanism-of-action is an involvement of the PP2A which, once released by PEP-010, could regulate expression and/or activity of different intracellular factors leading to caspases activation and cell death.The identification of the major molecular features involved in PEP-010 mechanism-of-action, were instrumental to identify different pharmacodynamic biomarker candidates (e.g. active caspase-3). Hence, such biomarkers could be useful in clinical practice to monitor the effect of PEP-010 at molecular level. We have compared specific features related to the mechanism-of-action of PEP-010 in sensitive (MDA-MB-231, IGROV1) and not sensitive cell models of different tumor origins and in tissue sections derived from Patient-Derived Xenografts models of breast cancer treated or not with PEP-010. Widely used techniques as immunofluorescent staining and immunohistochemistry were employed, making these results easily transferable in clinical routine.Taken together, our pre-clinical data showed the potential of PEP-010 as an anti-cancer peptide on a wide variety of malignancies and enabled the identification of pharmacodynamic biomarker candidates, important to ease the clinical development. Citation Format: Rayan Farhat, Laura Dadon, F Nemati, A Rebollo, D Decaudin, Joelle Wiels, Catherine Brenner, Diego Germini. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6129.
Abstract 3277: <i>In vivo</i> CRISPR screening identifies <i>PTDSS1</i> as a potential combinatorial target to improve immune checkpoint therapy response
Authors: Jielin Liu, Swetha Anandhan, Sreyashi Basu, Yulong Chen, Sangeeta Goswami, Ashwat Nagarajan, Shelley Herbrich, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma
Journal: Cancer Research (2023)

Abstract Immune checkpoint therapy (ICT) has recently revolutionized the treatment paradigm for various types of cancer. However, despite the unprecedented safety and efficacy profile compared to traditional treatment options, many patients do not respond to ICT, highlighting the urgent need for novel strategies to improve ICT efficacy. Here, we used a pooled in vivo CRISPR knockout screening in a mouse bladder cancer model treated with immune checkpoint inhibitor to discover targets that may improve immunotherapy response. Our data identified Ptdss1, which encodes phosphatidylserine synthase 1, as a potential regulator of anti-PD-1 response. Depletion of Ptdss1 not only increased tumor cell immunogenicity and response to interferon gamma, but also facilitated development of an anti-tumor microenvironment. Ptdss1 depletion in tumor cells increased effector CD8+ T cells cytolytic function, decreased regulatory T cells activation and inhibitory function, increased frequency of iNOS+ myeloid cells and induced macrophage M2-to-M1 polarization. Ptdss1 knockdown induced changes in the tumor microenvironment were further amplified when combined with anti-PD-1 treatment, which translates into better tumor control and prolonged animal survival in mouse bladder cancer model. Together, our results provide insights on a new therapeutic strategy for overcoming resistance to immune checkpoint therapy through combination of PTDSS1 inhibition and PD-1 blockade. Citation Format: Jielin Liu, Swetha Anandhan, Sreyashi Basu, Yulong Chen, Sangeeta Goswami, Ashwat Nagarajan, Shelley Herbrich, Liangwen Xiong, Baoxiang Guan, Padmanee Sharma. In vivo CRISPR screening identifies PTDSS1 as a potential combinatorial target to improve immune checkpoint therapy response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3277.